((R)-3-amino-1-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-butan-1-one, is a dipeptidyl peptidase-4 (DPP-IV) enzyme modulator and is useful in Type 2 diabetes therapy. The compound is also known as Sitagliptin. Sitagliptin also exists as its acid salts. The salt of sitagliptin has the following chemical structure:

The phosphate salt of sitagliptin has the following chemical structure:

In a specific embodiment, sitagliptin is a monohydrate of the phosphate salt of sitagliptin, and has the following chemical structure:

Sitagliptin is used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment of diabetes mellitus type II. The benefit of this medicine is its lower side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values.
Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones that are released in response to a meal (J Clin Pharmacol 46 (8): 876-86). By preventing GLP-1 and GIP inactivation, GLP-1 and GIP are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminish, thus tending to prevent an “overshoot” and subsequent low blood sugar (hypoglycemia) that is seen with some other oral hypoglycemic agents (Wikipedia).
International Application Publication No. WO2003/004498 and U.S. Pat. No. 6,699,871, describe the use of sitagliptin and analogs, and the composition thereof.
Several processes for the synthesis of sitagliptin are known. For example, International Application Publication WO2004/085661 discloses the preparation of sitagliptin using S-phenylglycine amide as a chiral auxiliary.
International Application Publication No. WO2004/087650 discloses the preparation of sitagliptin using the chiral benzyloxylazetidinone as an intermediate.
International Application Publication Nos. WO2004/085378, WO2005/097733, and WO2006/081151 disclose the preparation of sitagliptin which involves an enantioselective reduction of the intermediate chiral enamine in the presence of specific catalysts.
International Application Publication No. WO2009/085990 discloses the preparation of sitagliptin using various chiral auxiliaries, such as chiral resolving agents.
While these methods are useful for preparing Sitagliptin, alternative methods of the preparation, particularly for manufacturing scale production, are desirable.
Citation of any reference in this application is not to be construed as an admission that such reference is prior art to the present application.